OBJECTIVE: To investigate the efficacy and mechanism of the Qingre Huayu Fang(清热化瘀方) on atherosclerotic vulnerable plaque in apolipoprotein E(Apo E) knockout mice through the ubiquitin proteasome pathway.METHODS: Sixty 8-week-old C57BL/6J Apo E knockout mice were fed a high-fat for 12 weeks and randomly divided into four treatment groups(n = 15 each): high-fat control, bortezomib(a proteasome inhibitor), bortezomib combined with Qingre Huayu Fang, and Qingre Huayu Fang alone. Aortic sections were examined for plaque development, inflammatory cell infiltration, type Ⅰ/Ⅲ collagen expression and immunohistochemical staining of CD40L, nuclear factor-kappa B(NF-κB)/P65 and ubiquitin.RESULTS: Mice in the high-fat control group had obvious atherosclerosis, with increased aortic plaque area. The degree of atherosclerosis of the atherosclerotic plaque was reduced in all of the treatment groups that received bortezomib and/or Duzhong(Cortex Eucommiae) Qingre Huayu. The expression of NF-?B, CD40L and ubiquitin were all reduced in the group that received combination bortezomib + Qingre Huayu Fang.CONCLUSION: The Qingre Huayu Fang inhibited aortic atherosclerosis in mice through a mechanism that may involve inhibition of the ubiquitin proteasome pathway.